RU2264814C2 - Antihistamine pharmaceutical composition - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: the present innovation deals with applying antihistamine preparation named mebhydrolin. It is suggested to apply pharmaceutical composition that includes therapeutically efficient quantity of mebhydrolin and target additives as sugar, starch, polyvinyl pyrrolidone and salt of stearic acid. Pharmaceutical composition is designed in tableted form. The innovation provides correspondence of mebhydrolin tablets against all the standards of State pharmacopoeia XI, decreased quantity of additional substances and expiry period of 3 yr, not less.

EFFECT: higher efficiency of application.

5 cl, 3 ex, 2 tbl

Description

The invention relates to medicine, specifically to the drug mebhydroline (trade names diazolin, insidyl, omeril) (Mashkovsky M.D. Medicines t. 1, ed. 12th, M., 1993, p. 353), which has antihistamine action and used in various allergic diseases (hay fever, urticaria, vasomotor rhinitis, itchy dermatoses, etc.). Mebhydroline is a blocker of H ₁ receptors, but unlike most other drugs, the same effect does not have a sedative and hypnotic effect, which allows it to be used in cases where the inhibitory effect on the central nervous system is undesirable. Typically, the drug is well tolerated, but in some cases it can cause irritation of the gastric mucosa and is therefore contraindicated in patients with peptic ulcer of the stomach and duodenum, inflammatory diseases of the gastrointestinal tract.

Due to adverse environmental conditions, poor nutrition, deterioration in the quality of drinking water, etc., the number of allergic diseases increases sharply, including among patients suffering from diseases of the gastrointestinal tract. Therefore, a search is underway for the creation of a dosage form of mebhydroline, which would eliminate this undesirable side effect.

In the patent of the Russian Federation 2121347, 1998, a pharmaceutical composition is described containing a combination of diazolin with zinc sulfate, which, as the authors indicate, when used together, have a synergistic effect. In specific embodiments of the invention, low molecular weight polyvinyl pyrrolidone, methyl cellulose and magnesium stearate are indicated as auxiliary substances for preparing a solid dosage form. In the patent of the Russian Federation 2140268, 1999, a combination of diazolin with zinc sulfate is described containing polyvinylpyrrolidone, potato starch and calcium stearate as target additives.

At the same time, zinc-containing compounds have a strong and ambiguous effect on the patient's body, caused by the participation of zinc in various physiological and pathological processes. With the internal use of zinc preparations, especially in children, adverse reactions were noted (nausea, vomiting, heaviness and pain in the epigastric region). Therefore, the use of its complex with another active component (zinc sulfate) instead of diazolin is not always acceptable.

An attempt to mitigate the side irritating effect of diazolin, making it in the form of dragees, was unsuccessful. It has been established that the bioavailability of diazolin in dragees relative to an orally administered substance is 28-30% (Nazarov U.Z., Tischenkova I.F., Kholodov L.E., Chemical and Pharmaceutical Journal, 25 (12), 11 -13, 1991). With a single dose of the drug, the pharmacological effect occurs very slowly, which may be due to the poor solubility of diazolin in water. It should be noted that during the “Dissolution” test, less than 75% of diazolin is released from the dragee in 45 minutes, which does not meet the requirements of the current State Pharmacopoeia of the 11th edition.

In the patent of the Russian Federation 2160095, 2000, diazolin tablets are proposed in which the product of the interaction of the substance of diazolin with β-cyclodextrin in the presence of excipients: stearic acid, talc, starch and aerosil in the following ratio per tablet in g is tabletted:

Diazolin 0,046-0,054 β-cyclodextrin 0.13-0.15 Stearic acid 0.0021-0.0025 Talc 0.0063-0.0073 Starch 0.0056-0.0065 Aerosil 0.021-0.025

As indicated in the patent, this composition allows to obtain diazolin tablets with high bioavailability and significantly reduced, in comparison with the substance and other dosage form, the irritating effect on the gastric mucosa. However, the disadvantage of this composition is the excess of certain requirements of the State Pharmacopoeia of the 11th edition: for example, the content of aerosil in a tablet is 10.081% (at a rate of not more than 10%), the content of stearic acid is 1.008% (at a rate of not more than 1%), a large amount of excipients - an average of 356.3% by weight of the active substance (diazolin), as well as a shelf life of 18 months.

The objective of this invention is to develop an antihistamine pharmaceutical composition based on mebhydrolin, which would meet all the regulatory requirements of the Gosfarmakopei XI ed., Including the percentage of excipients in tablets, contained fewer excipients and would have a shelf life of at least three years.

This is achieved by an antihistamine pharmaceutical composition containing an effective amount of mebhydrolin and target additives, which are sugar, starch, polyvinylpyrrolidone and a stearic acid salt in the following ratio of components,% by weight of the active substance:

Sugar 84.8-105.6 Starch 74.7-91.3 Polyvinylpyrrolidone 16.2-21.8 Stearic acid salt 2.7-3.3

Milk sugar is mainly used as sugar, and potato and / or corn starch is suitable as starch. Collidone is mainly used as polyvinylpyrrolidone, and magnesium or calcium salts are used as the stearic acid salt.

The proposed ratio of active substance and target additives is found experimentally and is optimal, ensures that all the requirements of the Gosfarmakopei XI ed. and allows you to have a shelf life of mebhydroline of at least 3 years (see table 2). In addition, the amount of targeted additives per unit of active substance (mebhydrolin) is on average 200% (see table).

Going beyond the lower limit of the ratios of the basic substance and target additives leads to a deterioration of the technological parameters of the process for preparing the dosage form of mebhydroline, and an increase in target additives is impractical, since it reduces the quality of some indicators of the pharmacopeia product.

The dosage form of mebhydrolin is in the form of a solid dosage form, mainly in the form of a tablet.

The resulting tablets meet all regulatory requirements and have a shelf life of at least 3 years (see table 2).

A comparative toxicological study was conducted on the bioequivalence of mebhydrolin obtained according to the invention and a reference preparation. A subchronic experiment was conducted on randomly bred male rats with an average weight of 229 ± 7 g. Compared preparations were administered intragastrically at doses of 35.0 (therapeutic) and 175.0 mg / kg once a day for 2 weeks. According to the results of the experiment, experimental animals did not reveal an irritating effect on the mucous membrane of the gastrointestinal tract and a significant effect on integral indicators (weight gain, consumption of feed, water, and general behavior of animals). The drugs in the studied doses did not cause structural disorders in organs and tissues.

Thus, the conducted studies, firstly, confirm the bioequivalence of the action of the tablet form of mebhydroline and the reference drug on the animal organism, and secondly, the absence of the irritating effect of the proposed antihistamine pharmaceutical composition of mebhydroline.

The following examples illustrate the invention.

Example 1. A mixture of 100 g of mebhydroline powder, 83 g of corn starch and 96 g of milk sugar is moistened with a 15% aqueous solution of polyvinylpyrrolidone (from 18.15 g of collidone), mixed until uniform and passed through a granulator. The granulate is dried at 30-50 ° C to a residual moisture content of 2.0-3.0%. The dried granules are passed through a granulator and dusted with calcium stearate in an amount of 2.73 g and tabletted on a press. Get 1875 tablets with an average weight of each tablet of 0.152 g and an average content of 0.05 g of mebhydrolin in one tablet. The resulting tablets meet all the requirements of the State Pharmacopoeia XI ed. and have a shelf life of more than 3 years (see table 1).

Example 2. Obtaining tablets of mebhydroline is carried out according to example 1 based on 100 g of mebhydroline, 91.3 g of potato starch, 84.8 g of sugar, 16.2 g of collidone and 2.7 g of magnesium stearate. 1793 tablets are obtained with an average weight of one tablet of 0.147 g and an average content of 0.052 g of mebhydrolin in one tablet. The resulting tablets meet all regulatory requirements and have a shelf life of 3 years (see table 1).

Example 3. Obtaining tablets of mebhydroline is carried out according to example 1 based on 100 g of mebhydroline, 74.7 g of potato starch, 105.6 g of milk sugar, 21.8 g of collidone and 3.2 g of magnesium stearate. 977 tablets are obtained with an average weight of 0.31 g and an average content of 0.098 g of mebhydroline in one tablet. The resulting tablets have a shelf life of 3 years and meet all regulatory requirements (see table 1).

Table 1 Component loading No. p / p Targeted Supplements Name The amount,% by weight of the active substance Example 1 Example 2 Example 3 1 Sugar 96.0 84,8,5 105.6 2 Starch 83.0 91.3 74.7 3 Polyvinylpyrrolidone 18.1 16,2 21.8 4 Stearic acid salt 2.9 2.7 3.3

table 2 Quality of mebhydrolin tablets Name
quality indicator Requirements
qualities Actual figures Example 1 Example 2 Example 3 Average weight 0.15 ± 17.5%, i.e. 0.152 0.147 tablets, g from 0.138 to 0.161 0.3 ± 5%, i.e. 0.31 0.285 to 0.315 Mass deviation 20 from 20 individual tablets no more than 5 -1.8 + 1.9 -1.9 + 2.1 -2.2 + 2.1 from the average weight,% Disintegration, min No more than 15 8 6 10 Dissolution% Not less than 75 100.0 98.8 88.0 in 45 min Strength kg Not standardized 15.8 15.4 16.1 Megid content 0.05 ± 7.5%, i.e. 0.05 0,052 - roll in 1 table., g from 0.046 to 0.054 0.1 ± 5%, i.e. - - 0,098 from 0.095 to 0.105 Stearic salt No more than 1% 0.7 0.85 0.73 acid Shelf life 3 years more than 3 years 3 years 3 years

Claims (6)

1. An antihistamine pharmaceutical composition comprising mebhydroline and target additives as an active ingredient, characterized in that it contains a therapeutically effective amount of mebhydroline, and sugar, starch, polyvinylpyrrolidone and a stearic acid salt as target additives in the following ratio of components,% by weight of the active substance substances: Sugar 84.8-105.6 Starch 74.7-91.3 Polyvinylpyrrolidone 16.2-21.8 Stearic acid salt 2.7-3.3 2. The pharmaceutical composition according to claim 1, characterized in that it contains potato and / or corn starch as starch. 3. The pharmaceutical composition according to claim 1 or 2, characterized in that it contains mainly milk sugar as sugar. 4. The pharmaceutical composition according to claim 1 or 2, characterized in that as the salt of stearic acid, it contains a magnesium or calcium salt. 5. The pharmaceutical composition according to claim 1, characterized in that it is made in the form of a solid dosage form. 6. The pharmaceutical composition according to claim 5, characterized in that it is made mainly in the form of tablets.